The present invention relates to an agent for inducing apoptosis which comprises a tetrocarcin derivative as an active ingredient and which is useful for preventive and/or therapeutic treatment of cancers, AIDS or the like.
Cell death is considered to be caused by two types of mechanisms, and one of them is the cell death called necrosis. This process is morphologically characterized by marked expansion of mitochondria, swelling of cytoplasm, degeneration of nuclei and subsequent decay and autolysis of cells, and the process occurs passively and accidentally. Necrocytosis is generally observed when cells receive physical injury, chemical toxicoids or the like.
The other type is the cell death called apoptosis or programmed cell death (Kerr, J. F. and Wyllie, A. H., Br. J. Cancer, 26, pp.239-257, 1972). This cell death is considered to occur under various physiological conditions. The morphological characteristics thereof include absence of contact with neighboring cells, concentration of cytoplasm, pyknosis of chromatin participating in endonuclease activity and pyknosis of nuclei, segmentation of nuclei and so forth, and disappearance of microvilli of cell surfaces, smoothing of cell surfaces (membrane blebbing on cell surfaces) and the like are also observed. Further, a phenomenon is also observed in which nucleosome units of DNA are fragmented into DNAs of 180 to 200 base length by the endonuclease activity. The mechanism of apoptosis is explained as a mechanism of phagocytosis for final fragments of apoptic cells by neighboring cells.
Apoptosis is essential in many physiological processes including germ development and clonal selection in an immune system (Ito, N. et al., Cell, 66, pp.233-243, 1991), and the process is initiated by various stimulations such as removal of glucocorticoid hormones or certain types of growth factors in immature thymocytes (Watanabe-Fukunaga, R. et al., Nature, 356, pp.314-317, 1992). The apoptosis is also reported to be induced by cell damage by cytotoxic T cells, hormone-dependent tissue atrophy, irradiation with radiation, NK cells, killer cells, cytokines such as a tumor necrosis factor (TNF) and so forth (Wyllie, A. H. et al., Int. Rev. Cytol., 68, pp.251-306, 1980; Duvall, E. and Wyllie, A. H., Immunology Today, 7, pp.115-119, 1986; Sellins, K. S. et al., J. Immunol., 139, pp.3199-3206, 1987; Yamada, T. et al., Int. J. Radiat. Biol., 53, pp.65-75, 1988; Wyllie, A. H., Nature, 284, pp.555-556, 1980; Schmid, D. S. et al., Proc. Natl. Acad. Sci. USA, 83, pp.1881-1885, 1986; Hiserodt, J. C. et al., J. Immunol., 129, pp.1782-1787, 1982; Howell, D. M. et al., J. Immunol., 140, pp.689-692, 1988; Gillian, B. et al., Eur. J. Immunol. 17, pp.689-693, 1987).
In addition, certain kinds of antibodies such as anti-CD3 antibodies, anti-Apo-1 antibodies and anti-Fas antibodies also induce apoptosis (Trauth, B. C. et al., Science, 245, pp.301-305, 1989; Smith, C. A. et al., Nature, 337, pp.181-184, 1989; Tadakuma, T. et al., Eur. J. Immunol., 20, pp.779-784, 1990), and apoptosis has also been verified in findings of spontaneous regression of malignancies (Yasuo Nakamura et al., Rinsho Hifuka, 35, pp.289-295, 1981).
A series of cysteine proteases called caspase is known to be activated in the process of apoptosis, which is preserved over the species as a biochemical mechanism involved in the induction of apoptosis (Miura, M. et al., Cell, 75, pp.653-660, 1993; Nicholson, D. W. et al., Nature, 376, pp.37-43, 1995). It has been elucidated that degradation of plural protein substrates by the aforementioned caspase triggers the induction of apoptosis, and an increase of the enzymatic activity of caspase is a biochemical sign indicating induction of apoptosis (Enari, M. et al., Nature, 391, pp.43-50, 1998; Sakahira, H. et al., Nature, 391, pp.96-99, 1998).
It is known that the process of the aforementioned caspase activation is suppressed by proteins belonging to the Bcl-2 family, e.g., Bcl-2 and Bcl-XL, and when the expression levels of the proteins of the Bcl-2 family increase, the activation of caspase due to various apoptosis inductive stimulations is suppressed, thereby apoptosis fails to be induced (Hockenbery, D. M., BioEssays, 17, pp.631-638, 1995; Reed, J. C., J. Cell. Biol., 124, pp.1-6, 1994; Steller, H., Science, 267, pp.1445-1449, 1995).
As diseases caused by resistance to apoptosis due to the increase of expression levels of the Bcl-2 family proteins, examples include human follicular B-type lymphoma (Tsujimoto, Y. et al., Science, 228, pp.1440-1443, 1985), non-hormone dependent prostatic cancer (McDonnell, T. et al., Cancer Res., 52, pp.6940-6944, 1992; Colombel, M. et al., Am. J. Pathlogy, 143, pp.390-400, 1993), hormonotherapy resistant breast cancer (Leek, R. D. et al., Br. J. Cancer, 69, pp.135-139, 1994; Silverstrini, R. et al., J. National Cancer Inst., 86, pp.499-504, 1994), anticancer agent-resistant tumor (Ynis, J. J. et al., N. Engl. J. Med., 320, pp.1047-1054, 1989; Campos, L. et al., Blood, 81, pp.3091-3096, 1993), arteriosclerosis (Pollman, M. J. et al., Nature Med., 4, pp.222-227, 1998), Rheumatoid arthritis (Mueller- Ladner, U. et al., Arthritis and Rheumatism, 37 (suppl.) S163, 1994; Firestein, G. S. et al., J. Clin. Invest., 96, pp.1631-1638, 1995) and so forth.
Therapies by administration of antisense RNA for bcl-2 or bcl-XL have been reported as remedies for diseases resulting from the increase of expression levels of Bcl-2. However, no effective pharmacotherapy using a low molecular organic compound has been known so far (Webb, A. et al. Lancet, 349, pp.1137-1141, 1997; Ziegler, A. et al., J. National Cancer Inst., 89, pp.1027-1036, 1997; Jansen, B. et al., Nature Med., 4, pp.232-234, 1998; Pollman, M. J. et al., Nature Med., 4, pp.222-227, 1998).
Tetrocarcins are a class of antibiotics and are known to have an antibacterial and anti-cancer activity. Among them, tetrocarcin A has the following structure. 
In addition to the above tetrocarcin A, tetrocarcins B, C, D, E1, E2, F, F-1, F-2, G, H, I, J, K, L, M and so forth having structures similar thereto are known. The aforementioned compounds wherein the 9- and 21-positions are substituted with lower alkanoyloxy groups or wherein the 9-, 17- and 21-positions are substituted with lower alkanoyloxy groups are also included in the tetrocarcins. These tetrocarcins are described in the following patent documents (they are occasionally referred to using DC-11 as DC-11-A, DC-11-B and so forth without using the name of tetrocarcin): Japanese Patent Unexamined Publication (Kokai) Nos. 54-138501/1979, 55-79322/1980, 56-139500/1981, U.S. Pat. No. 4,346,075 (all for tetrocarcin A), Japanese Patent Unexamined Publication Nos. 56-115794/1981, 56-122392/1981 (both for tetrocarcin B), Japanese Patent Unexamined Publication Nos. 56-75500/1981, 56-122392/1981 (both for tetrocarcin C), Japanese Patent Unexamined Publication No. 56-122392/1981 (tetrocarcin D), Japanese Patent Unexamined Publication No. 57-38796/1982 (tetrocarcins E1 and E2), Japanese Patent Unexamined Publication No. 57-53498/1982 (tetrocarcins F, G and H), Japanese Patent Unexamined Publication No. 57-171997/1982 (tetrocarcins I, J, K, L and M), Japanese Patent Unexamined Publication No. 57-7479/1982 (tetrocarcins F-1 and F-2), and Japanese Patent Unexamined Publication 57-7479/1982 (compounds having lower alkanoyloxy groups at the 9- and 21-positions, and compounds having lower alkanoyloxy groups at the 9-, 17- and 21-positions).
The tetrocarcins are also known to have anti-Piroplasma activity (Japanese Patent Unexamined Publication Nos. 59-161317/1984 and 60-1129/1985). Furthermore, there are known several compounds as analogues of tetrocarcins [the family of BE-45722 (Japanese Patent Unexamined Publication No. 9-227587/1997, antibacterial activity), tetromycins (tetromycins A and B (Japanese Patent Unexamined Publication No. 8-165286/1996), tetromycins C1 to C5 (Japanese Patent Unexamined Publication No. 10-057089/1998), antibacterial activity), kijanimicins (Japanese Patent Publication (Kokoku) No. 3-27559/1991, EP33840A2, U.S. Pat. No. 4,375,542, antibacterial, anti-cancer, anti-parasitic and anti-inflammatory activities), BMY-42448 (U.S. Pat. No. 5,082,933, anti-tumor activity), macrocyclic lactone produced by a microorganism, S. aerocolongenes sub sp. antibiotics SCC 1886, ATCC55003 (U.S. Pat. No. 5,342,852, antibacterial activity), chlorothricins (Japanese Patent Unexamined Publication Nos. 2-174721/1990 and 2-275893/1990, hypolipidemic action), anthramycins (Japanese Patent Unexamined Publication Nos. 56-29595/1981, 56-108719/1981 and 56-139498/1981, antibacterial and anti-cancer activity), A88696C, D and F (Tetrahedron Lett., 34, pp.7857-7860, 1993, gastric ATP-ase inhibitory action), and PA-46101A and B (J. Antibiot., 43, pp.739-747, 1990, antibiotics)]. However, apoptosis induction activity of said compounds has not been known.
An object of the present invention is to provide an agent for inducing apoptosis. More specifically, the object of the present invention is to provide an agent for inducing apoptosis that can exert desired pharmacological effects on various diseases by apoptosis inducing action resulting from Bcl-2 inhibition. Another object of the present invention is to provide a medicament which comprises a substance having the aforementioned action as an active ingredient. More specifically, the object of the present invention is to provide a medicament useful for preventive and/or therapeutic treatment of cancers, AIDS, ARC (AIDS related conditions), osteoarthritis, autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematodes, collagenosis such as Sjxc3x6gren""s syndrome, arteriosclerosis or the like. A still further object of the present invention is to provide novel tetrocarcin derivatives useful as active ingredients of various medicaments such as anticancer agents and antibacterial agents.
The inventors of the present invention conducted various studies to achieve the aforementioned objects. As a result, they found that the compounds represented by the following general formula had action of inducing apoptosis and they were useful for preventive and/or therapeutic treatment of diseases including cancer and AIDS. The present invention was achieved on the basis of the aforementioned findings.
The present invention thus provides an agent for inducing apoptosis which comprises, as an active ingredient, a tetrocarcin derivative represented by the following general formula (I) or a physiologically acceptable salt thereof: 
wherein ---- represents a single bond or a double bond provided that two adjacent bonds are not simultaneously double bonds;
j and k represent 0 or 1;
R1, R2, R3, R7, R8, R9, R10, and R14 independently represent a hydrogen atom, a substituted or unsubstituted lower alkyl group, a formyl group or a carboxyl group; R4, R12, R13, and R15 independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, or a group represented by xe2x80x94[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m and p independently represent an integer of from 0 to 8, and R20, R21, and R22 independently represent a lower alkyl group or a substituted or unsubstituted aryl group);
R16, R17, and R18 independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, a group represented by xe2x80x94[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m, p, R20, R21, and R22 have the same meanings as those defined above), a substituted or unsubstituted lower alkoxyalkyl group, a formyl group, a carboxyl group, a substituted or unsubstituted lower alkoxycarbonyl group, a substituted or unsubstituted lower alkanoyloxyalkyl group, a group represented by xe2x80x94(CH2)rOSi(R23)(R24)(R25) (in the formula, r represents an integer of from 1 to 8, R23, R24, and R25 independently represent a lower alkyl group or a substituted or unsubstituted aryl group), a group represented by xe2x80x94CHxe2x95x90CHR26 (in the formula, R26 represents a substituted or unsubstituted lower alkoxycarbonyl group), a group represented by xe2x80x94CHxe2x95x90NOR27 (in the formula, R27 represents a hydrogen atom or a substituted or unsubstituted lower alkyl group), or xe2x80x94CH(X1R28)2 (in the formula, X1 represents an oxygen atom or a sulfur atom, and R28 represents a lower alkyl group or two of R28 are combined together to represent xe2x80x94(CH2)2xe2x80x94or xe2x80x94(CH2)3xe2x80x94), or R16 and R17 are combined together to represent an oxygen atom;
R11 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, or a group represented by xe2x80x94[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m, p, R20,
R21, and R22 have the same meanings as those defined above), or a group represented by the following formula (A): 
(in the formula, R29 represents a hydrogen atom or a lower alkyl group, R30 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyl group, or a substituted or unsubstituted lower alkoxycarbonyl group, and R31 represents a nitro group, a nitroso group, a hydroxyl group, or an amino group);
R19 represents a hydroxyl group, a substituted or unsubstituted lower alkoxyl group, or a substituted or unsubstituted lower alkanoyloxy group;
R5 and R6 are combined together to represent an oxygen atom or R6 and R6 independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, or a group represented by xe2x80x94[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m, p, R20, R21, and R22 have the same meanings as those defined above), or when R5 represents a hydrogen atom, R6 may be a group selected from the group consisting of the groups represented by the following formulas (B), (B-2), (C-1), (C-2), (D), and (E): 
(in the formula, ---- represents a single bond or a double bond, R32 represents a hydrogen atom, a formyl group, or a group represented by xe2x80x94CH2R32a, and R33, R34, R35, and R32a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, xe2x80x94OSi(R20a)(R21a)(R22a) (in the formula, R20a, R21a, and R22a have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, or a substituted or unsubstituted aralkylamino group); 
(in the formula, R35b represents a substituted or unsubstituted lower alkyl group, R32b represents a hydrogen atom, a formyl group, or a group represented by xe2x80x94CH2R32c, and R33b, R34b, and R32c independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, xe2x80x94OSi(R20a1)(R21a1)(R22a1) (in the formula, R20a1, R21a1, and R22a1 have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group or a substituted or unsubstituted aralkylamino group); 
(in the formula, ---- represents a single bond or a double bond, R36 represents a hydrogen atom, a formyl group, or a group represented by xe2x80x94CH2R36a, R41 represents a hydrogen atom or a group represented by xe2x80x94CH2R41a, and R37, R38, R39, R40, R41a, R42, and R36a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, xe2x80x94OSi(R20b)(R21b)(R22b) (in the formula, R20b, R21b, and R22b have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group or a substituted or unsubstituted aralkylamino group); 
(in the formula, ---- represents a single bond or a double bond, R43 represents a hydrogen atom, a formyl group or a group represented by xe2x80x94CH2R43a, R44 represents a hydrogen atom or a group represented by xe2x80x94CH2R44a, and R44a, R45, R46, R47, R48, R49, and R43a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, xe2x80x94OSi(R20c)(R21c)(R22c) (in the formula, R20c, R21c, and R22c have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, or a substituted or unsubstituted aralkylamino group); 
(in the formula, ---- represents a single bond or a double bond, R50 represents a hydrogen atom, a formyl group or a group represented by xe2x80x94CH2R50a, R58 represents a hydrogen atom or a group represented by xe2x80x94CH2R58a, R54 represents a hydrogen atom or a group represented by xe2x80x94CH2R54a, and R51, R52, R53, R54a, R55, R56, R57, R58a, R59, and R50a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, xe2x80x94OSi(R20d)(R21d)(R22d) (in the formula, R20d, R21d, and R22d have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, a substituted or unsubstituted aralkylamino group, or a group represented by the aforementioned formula (B)); and 
(in the formula, ---- represents a single bond or a double bond, R60 represents a hydrogen atom, a formyl group or a group represented by xe2x80x94CH2R60a, R61 represents a hydrogen atom or a group represented by xe2x80x94CH2R61a, R65 represents a hydrogen atom or a group represented by xe2x80x94CH2R65a, and R61a, R62, R63, R64, R65a, R66, R67, R68, R69, and R60a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, xe2x80x94OSi(R20e)(R21e)(R22e) (in the formula, R20e, R21e, and R22e have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, a substituted or unsubstituted aralkylamino group, or a group represented by the aforementioned formula (B)).
According to another aspect of the present invention, provided is a medicament which comprises the tetrocarcin derivative represented by the aforementioned formula (I) or a physiologically acceptable salt thereof as an active ingredient and which is used for preventive and/or therapeutic treatment of a disease which can be preventively and/or therapeutically treated by induction of apoptosis. Examples of the diseases include diseases resulting from increased expression of the Bcl-2 family proteins, for example, cancers, AIDS, ARC (AIDS related conditions), osteoarthritis, autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematodes, collagenosis such as Sjxc3x6gren""s syndrome, arteriosclerosis and so forth.
The aforementioned inducer and medicament are preferably provided in the form of a pharmaceutical composition comprising the tetrocarcin derivative represented by the aforementioned formula (I) or a physiologically acceptable salt thereof together with an additive for a pharmaceutical preparation. According to the present invention, further provided are use of the tetrocarcin derivative represented by formula (I) or a physiologically acceptable salt thereof for the manufacture of the aforementioned agent for inducing apoptosis or the aforementioned medicament; and a method for preventive and/or therapeutic treatment of a disease resulting from increased expression of the Bcl-2 family proteins, which comprises the step of administering a preventively and/or therapeutically effective amount of the tetrocarcin derivative represented by formula (I) or a physiologically acceptable salt thereof to a mammal including human.
According to a further aspect of the present invention, provided is a tetrocarcin derivative represented by the following formula (Ia) or a salt thereof: 
wherein R15a represents a hydroxyl group, xe2x80x94OSi(R70)(R71)(R72) (in the formula, R70, R71, and R72 independently represent a lower alkyl group or a substituted or unsubstituted aryl group), a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted lower alkenoyloxy group or a substituted or unsubstituted aroyloxy group; R11a represents any one of the substituents defined for the aforementioned R15a, or a group represented by the following formula (F): 
R5a represents any one of the substituents defined for the aforementioned R15a, or a group selected from the group consisting of a group represented by the following formula (G): 
(in the formula, ---- represents a single bond or a double bond, R93 represents a hydrogen atom or a group represented by xe2x80x94CH2R93a, and R73, R74, R94, and R93a independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), a group represented by the following formula (G-2): 
(in the formula, R94b represents a substituted or unsubstituted lower alkyl group, R93b represents a hydrogen atom or a group represented by xe2x80x94CH2R93c, and R73b, R74b and R93c independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), a group represented by the following formula (H): 
(in the formula, ---- represents a single bond or a double bond, R95 represents a hydrogen atom or a group represented by xe2x80x94CH2R95a, R99 represents a hydrogen atom or a group represented by xe2x80x94CH2R99a, and R95a, R75, R96, R97, R98, R76 and R99a independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), a group represented by the following formula (J): 
(in the formula, ---- represents a single bond or a double bond, Rxcfx86represents a hydrogen atom or a group represented by xe2x80x94CH2R100a, R104 represents a hydrogen atom or a group represented by xe2x80x94CH2R104a, R105 represents a hydrogen atom or a group represented by xe2x80x94CH2R105a, and R100a, R77, R101, R102, R103, R104a, R105a, R79, R78, and R106 independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), and a group represented by the following formula (K): 
(in the formula, ---- represents a single bond or a double bond, R107 represents a hydrogen atom or a group represented by xe2x80x94CH2R107a, R111 represents a hydrogen atom or a group represented by xe2x80x94CH2R111a, R113 represents a hydrogen atom or a group represented by xe2x80x94CH2R113a, R114 represents a hydrogen atom or a group represented by xe2x80x94CH2R114a, and R107a, R80, R108, R109, R110, R111a, R113a, R81, R112, R114a, R82, R115, and R116 independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a);
R18a represents a formyl group, a group represented by xe2x80x94CHxe2x95x90CHR83 (in the formula, R83 represents any one of the substituents defined for the above R26), a group represented by xe2x80x94CHxe2x95x90NOR84 (in the formula, R84 represents any one of the substituents defined for the above R27), or a group represented by xe2x80x94CH(X2R85)2 (in the formula, X2 represents any one of the substituents defined for the above X1, and R85 represents any one of the substituents defined for the above R28); and
R19a represents a hydroxyl group or a substituted or unsubstituted lower alkoxyl group:
provided that:
the aforementioned derivative wherein R15a, R11a, and R5a represent a hydroxyl group, R18a represents a formyl group, and R19a represents a methoxy group is excluded; the aforementioned derivative wherein R15a and R5a independently represent a hydroxyl group or a lower alkanoyloxy group, R11a represents a hydroxyl group, a lower alkanoyloxy group, or a group represented by formula (F), R18a represents a formyl group, and R19a represents a hydroxyl group is excluded; a compound represented by the following formula (Ib): 
(in the formula,
R5b represents a group represented by Axcex1-Bxcex1-Bxcex2-Cxcex1 (A xcex1 substitutes for R5b at xe2x97xaf, Axcex1-Bxcex1 means that {circle around (1)} of Axcex1 and {circle around (2)} of Bxcex2 are bound to each other, and in the other definitions, {circle around (1)} and {circle around (2)} are bound to each other in the same manner) and R18b represents a formyl group;
R5b represents a group represented by Axcex1-Bxcex1-Cxcex2 and R18b represents a formyl group;
R5b represents a group represented by Cxcex3 (Cxcex3 substitutes for R5b at xe2x97xaf) and R18b represents a formyl group;
R5b represents a group represented by Cxcex5 (C"Egr" substitutes for R5b at xe2x97xaf) and R18b represents a formyl group;
R5b represents a group represented by Axcex1-Cxcex1 and R18b represents a formyl group;
R5b represents a group represented by Axcex1-Bxcex2-Cxcex2 and R18b represents a formyl group; or
R5b represents a group represented by Axcex1-Bxcex2-Bxcex2-Cxcex1 and R18b represents a formyl group) is excluded; and
a compound represented by the following formula (Ic): 
(in the formula, R15c, R81c, and R82c represents an acetoxy group and R19c represents a hydroxyl group, or R15c, R19c, R81c, and R82c represent a methoxy group) is excluded. The compound represented by the aforementioned formula (Ia) or a salt thereof is useful as, for example, an active ingredient of a medicament, preferably an active ingredient of an antibacterial agent, an anticancer agent, an anti-Piroplasma agent, an anti-parasitic agent, an anti-inflammatory agent, a hypolipidemic agent, an agent for inducing apoptosis or the like.
The meanings of the terms used in the specification are as follows. An alkyl group or a lower alkyl group as well as an alkyl portion or an alkylene, or a lower alkyl portion or a lower alkylene portion of the lower alkanoyloxy group, lower alkoxyl group, lower alkoxycarbonyloxy group, aroyloxyalkyl group, lower alkoxyalkyl group, lower alkoxycarbonyl group, lower alkanoyloxyalkyl group, lower alkanoyl group, aralkyloxy group, lower alkylamino group, lower alkanoylamino group, or aralkylamino group containing an alkylene portion or a lower alkylene portion may be linear or branched.
The alkyl group or an alkyl portion of a substituent containing the alkyl portion which is not specifically referred to as xe2x80x9clowerxe2x80x9d is herein used to mean those including a linear or branched alkyl group having 1 to 20 carbon atoms. As the alkyl portion or alkylene of the lower alkoxyalkyl group, aroyloxyalkyl group, or lower alkanoyloxyalkyl group, a linear or branched alkyl group having 1 to 20 carbon atoms may be used. More specifically, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, a n-nonyl group, a n-decyl group, a n-undecyl group, n-octadecyl group, corresponding alkylenes and so forth may be used.
The alkyl group or an alkyl portion of a substituent containing the alkyl portion which is specifically referred to as xe2x80x9clowerxe2x80x9d is herein used to mean those including a linear or branched alkyl group having 1 to 8 carbon atoms. As the lower alkyl portion of the lower alkyl group, lower alkylamino group, lower alkoxyl group, lower alkoxycarbonyloxy group, lower alkoxyalkyl group, lower alkoxycarbonyl group, lower alkanoyl group, lower alkanoyloxy group, lower alkanoyloxyalkyl group, and lower alkanoylamino group, a straight or branched alkyl group having 1 to 8 carbon atoms is preferred. More specifically, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group and so forth may be used.
As a lower alkenyl portion of the lower alkenoyloxy group, a linear or branched alkenyl group having 2 to 8 carbon atoms may be used. More specifically, for example, a vinyl group, an allyl group, a crotyl group, a prenyl group, a 3-butenyl group, a 2-pentenyl group, a 4-pentenyl group, a 2-hexenyl group, a 5-hexenyl group and so forth may be used as the lower alkenyl portion.
As an aryl portion of the aryl group or a substituent containing an aryl portion (the aryloxy group, arylamino group, arylsulfonyloxy group, aroyloxy group, aroyloxyalkyl group, aroylamino group), monocyclic or bi- or tricyclic aryl groups may be used. The ring may be a condensed ring. The number of carbon atoms constituting the ring is preferably about 6 to 14. More specifically, examples of the aryl group include, for example, a phenyl group, a naphthyl group, an antholyl group and so forth.
As an aralkyl portion of the aralkyloxy group or aralkylamino group, an aralkyl group consisting of a combination of the aforementioned lower alkylene group and the aryl group may be used. Aralkyl groups having 7 to 15 carbon atoms, for example, a benzyl group, a phenethyl group, a benzhydryl group, a naphthylmethyl group and so forth may be suitably used. As an heteroaryl portion of the heteroaroylamino group, a monocyclic or bi- or tricyclic heteroaryl group may be used, and the ring may be a condensed ring. The number of ring-constituting atoms is preferably about 5 to 14, and the ring may contain one or more hetero atoms selected from, for example, the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. As the heteroaryl portion, for example, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a thiadiazolyl group, a pyridyl group, an indolyl group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, a thiazolyl group, a benzothiazolyl group, a benzimidazolyl group, an oxazolyl group and so forth may be used.
Where a functional group is referred to as xe2x80x9csubstituted or unsubstitutedxe2x80x9d, the definition is herein used to mean that the functional group may have one or more substituents which may be the same or different. Examples of substituents substituting on an alkyl portion or an alkylene portion, a lower alkyl portion or a lower alkylene portion, or the lower alkyl group, lower alkanoyloxy group, lower alkoxyl group, lower alkoxycarbonyloxy group, lower alkenoyloxy group, lower alkoxyalkyl group, lower alkoxycarbonyl group, lower alkanoyloxyalkyl group, lower alkanoyl group, lower alkylamino group, or lower alkanoylamino group are one to three substituents selected from the group consisting of a halogen atom (xe2x80x9chalogen atomxe2x80x9d used in this specification may be any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom), a hydroxyl group, a formyl group, a carboxyl group, a carbamoyl group, a mercapto group, an amino group, a mono- or di(loweralkyl)amino group, a nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkoxyalkoxy group, a lower alkoxyalkoxyalkoxy group, a lower alkoxycarbonyl group, a lower alkylthio group (a lower alkyl portion of the lower alkylthio group is the same as that defined above), a lower alkanoyl group, and a lower alkanoyloxy group. The lower alkyl group of the mono- or di(loweralkyl)amino group is the same as the aforementioned lower alkyl group. The lower alkyl group, lower alkoxyl group, lower alkoxycarbonyl group, lower alkanoyl group, and lower alkanoyloxy group are the same as those defined above. An lower alkoxy portion of the lower alkoxyalkoxy group and lower alkoxyalkoxyalkoxy group is the same as the aforementioned lower alkoxyl group, and an alkoxy portion and an alkoxy portion of an alkoxyalkoxy portion mean a linear or branched alkoxy having 1 to 20 carbon atoms derived from a linear or branched alkyl group having 1 to 20 carbon atoms.
Examples of substituents that substitute on ring moieties of the substituted aroylamino group, substituted aroyloxy group, substituted aroyloxyalkyl group, substituted aryl group, substituted arylamino group, substituted aryloxy group, substituted arylsulfonyloxy group, substituted aralkylamino group, substituted aralkyloxy group, substituted heteroaroylamino group and so forth are one to four substituents selected from the group consisting of a halogen atom, a hydroxyl group, a formyl group, a carboxyl group, a carbamoyl group, a mercapto group, an amino group, a mono- or di(loweralkyl)amino group, a nitro group, a lower alkyl group, a lower alkoxyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkanoyl group, an aryl group, and a lower alkanoyloxy group. When the rings have two or more substituents, they may be the same or different. The lower alkyl in the mono- or di(loweralkyl)amino group is the same as the aforementioned lower alkyl. The lower alkyl group, lower alkoxyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkanoyl group, aryl group, and lower alkanoyloxy group are the same as those defined above.
As the active ingredient of the medicament of the present invention, the compound represented by the aforementioned formula (I) in the free form as well as a physiologically acceptable salt thereof may be used. Examples of the salts include acid addition salts such as inorganic acid salts and organic acid salts; base addition salts such as metal salts, ammonium salts, and organic ammonium salts; and amino acid addition salts. Examples of the acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, and phosphates, and organic acid salts such as formates, acetates, benzoates, maleates, fumarates, succinates, tartrates, citrates, oxalates, methanesulfonates, p-toluenesulfonates, aspartates, and glutamates. Examples of the metal salts include, for example, alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and so forth. Examples of the ammonium salts include an ammonium, a tetramethylammonium and so forth, and examples of the organic ammonium salts include addition salts of morpholine, piperidine and so forth. Examples of the amino acid addition salts include, for example, addition salts of glycine, phenylalanine, lysine and so forth.
The compounds represented by the aforementioned formulas (I) and (Ia) have asymmetric carbon atoms, and accordingly, stereoisomers such as optically active compounds and diastereoisomers exist. As the active ingredients of the medicaments of the present invention, any substances including stereoisomers in pure forms, any mixtures of stereoisomers, racemates and so forth may be used. Where the compounds represented by the formulas (I) and (Ia) have an alkenyl group, the group may be in either of Z- or E-configuration. Where the compounds have a carbon/nitrogen double bond, they may be either a syn-isomer or anti-isomer as for the syn/anti isomerism resulting from the carbon/nitrogen double bond. As the active ingredients of the medicaments of the present invention, any of the geometrical isomers in pure forms and mixtures of the geometrical isomers may be used. As the active ingredients of the medicaments of the present invention, the compounds represented by the aforementioned formulas (I) and (Ia) and salts thereof, as well as any hydrates thereof and any solvates thereof may be used. Although the types of solvents that form the solvates are not particularly limited so long as they are physiologically acceptable solvents. For example, ethanol and so forth may be used.
Typical compounds of formula (I) and formula (Ia) preferably used as the active ingredients of the medicaments of the present invention will be shown below. However, the active ingredients of the medicaments of the present invention are not limited to these compounds.
Compounds 1, 6, 8, and 12 are disclosed in Japanese Patent Unexamined Publication No. 57-38796/1982, and Compounds 2, 9, 10, and 11 are disclosed in Japanese Patent Unexamined Publication No. 57-7479/1982. Further, Compound 3 is disclosed in the 23rd Symposium of Naturally Occurring Substances, Abstract 584 (1980), and Compounds 4, 5, and 7 are disclosed in Japanese Patent Unexamined Publication No. 57-53498/1982. Compounds 13, 14, 15, 18, and 19 are disclosed in Japanese Patent Unexamined Publication No. 57-171997/1982, and Compounds 16 and 17 are disclosed in Japanese Patent Unexamined Publication No. 56-122392/1981. Further, methods for producing novel compounds of formula (Ia) falling within the scope of formula (I) are explained in the specification, and specific methods for producing said novel compounds are described in detail in Examples. Therefore, those skilled in the art can easily prepare any compounds falling within the scope of formula (I).
The compounds represented by the aforementioned formula (I) and the physiologically acceptable salts thereof have an apoptosis inducing action, and they may be used as medicaments for preventive and/or therapeutic treatment of diseases that can be preventively and/or therapeutically treated by the induction of apoptosis. Further, they can also be used as reagents for inducing apoptosis in the fields of biochemistry, genetic engineering and so forth. While it is not intended to be bound by any specific theory, the medicaments of the present invention have an action for inducing apoptosis by activating caspase, which is suppressed by increased expression of proteins belonging to the Bcl-2 family. The apoptosis inducing action of the compounds represented by the aforementioned formula (I) or physiologically acceptable salts thereof can easily be confirmed by the methods specifically shown in Examples of the specification.
The term xe2x80x9capoptosis inducing actionxe2x80x9d or similar terminologies thereof herein used should be construed in their broadest sense including an apoptosis inducing action of the compound represented by formula (I) or a physiologically acceptable salt thereof, per se, as well as an enhancing action on apoptosis induction by various anticancer agents or anti-Fas antibodies, an enhancing action on the process of already induced apoptosis and so forth. The medicaments of the present invention may be used for preventive and/or therapeutic treatment of diseases resulting from increased expression of the Bcl-2 family proteins, for example, cancers, AIDS, ARC (AIDS related conditions), osteoarthritis, autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematodes, collagenosis such as Sjxc3x6gren""s syndrome, arteriosclerosis and so forth. However, diseases treatable by the medicaments of the present invention are not limited to the diseases exemplified above.
One or more of substances, per se, selected from the group consisting of the compounds of formula (I) and physiologically acceptable salts thereof, and hydrates thereof and solvates thereof may be administered as the medicaments of the present invention. It is generally desirable, however, that they are administered as a pharmaceutical composition comprising the aforementioned substance as the active ingredient together with one or more kinds of pharmaceutical additives. Types of the pharmaceutical compositions can be suitably chosen from various kinds of formulations suitable for oral administration or parenteral administration depending on the type of the active ingredient, purpose of administration and so forth. Although doses and administration frequencies of the medicaments of the present invention are not particularly limited, it is desirable to appropriately increase or decrease the dose or frequency depending on a dosage form, the age, body weight and conditions of a patient and so forth. In general, they are preferably administered once to four times a day in an amount of 0.01 to 20 mg/kg per day for adults. The medicaments of the present invention may be used in combination with other drugs such as anticancer agents, antibacterial agents, anti-inflammatory agents or the like. Pharmaceutical compositions containing the active ingredient of the present invention and an active ingredient having the aforementioned efficacy may be administered.
Examples of formulations suitable for oral administration include, for example, tablets, capsules, powders, granules, subtilized granules, solutions, suspensions, syrups, chewable tablets and so forth. Examples of formulations suitable for parenteral administration include, for example, injections for intravenous administration, intramuscular administration, or subcutaneous administration, drip infusions, eye drops, ear drops, suppositories, ointments, creams, transdermal preparations, transmucosal preparations, inhalants, patches and so forth. However, formulations of the medicaments of the present invention are not limited to these examples. These formulations are preferably prepared as unit dosage forms.
For the manufacture of the pharmaceutical compositions, one or more kinds of pharmaceutical additives widely used in the art may be used. The pharmaceutical additives may be chosen by those skilled in the art depending on the forms of formulations, and the formulations can be prepared in a conventional manner. For the manufacture of tablets, for example, excipients such as lactose, glucose, sucrose, mannitol and methylcellulose, disintegrating agents such as starch, sodium arginate, carboxymethylcellulose calcium and crystalline cellulose, lubricants such as magnesium stearate and talc, binders such as gelatin, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose and methylcellulose, surfactants such as sucrose fatty acid esters and sorbit fatty acid esters and so forth may be used in a conventional manner. Tablets containing 15 to 300 mg of the active ingredient per tablet are preferred.
For the manufacture of granules, for example, excipients such as lactose and sucrose, disintegrating agents such as starch, binders such as gelatin and so forth may be used in a conventional manner. For the manufacture of powdered drugs including powders, for example, excipients such as lactose and mannitol and so forth may be used in a conventional manner. For the manufacture of capsules, for example, gelatin, water, sucrose, gum arabic, sorbit, glycerol, crystalline cellulose, magnesium stearate, talc and so forth may be used in a conventional manner. Capsules containing 15 to 300 mg of the active ingredient per capsule are preferred. For the manufacture of syrups, for example, saccharides such as sucrose, water, ethanol and so forth may be used in a conventional manner.
For the manufacture of ointments, for example, ointment base materials such as Vaseline, liquid paraffin, lanolin, and macrogol, emulsifiers such as sodium lauryl lactate, benzalkonium chloride, sorbitan mono-fatty acid esters, carboxymethylcellulose sodium, gum arabic and so forth may be used in a conventional manner. For the manufacture of injections, for example, solvents such as water, physiological saline, vegetable oils (e.g., olive oil, peanut oil and the like), ethyl oleate, and propylene glycol, solubilizers such as sodium benzoate, sodium salicylate, and urethane, isotonic agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-hydroxybenzoate, and chlorobutanol, antioxidants such as ascorbic acid and sodium pyrosulfite and so forth may be used in a conventional manner.
According to the another aspect of the present invention, novel compounds represented by formula (Ia) are provided. Methods for producing the compounds of the present invention are not particularly limited. For example, they can be synthesized according to the reaction steps explained below, and specific examples are specifically explained in detail in Examples of the specification. As for the preparation methods explained below, where the defined groups are reactive under conditions for carrying out the methods or they are not suitable for carrying out the methods, the preparation of desired compounds may be facilitated by introduction and removal of protective groups which are conventionally used in the field of synthetic organic chemistry (see, for example, T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc. (1981)). Further, the order of the reaction steps such as steps of introducing functional groups may be changed as required.
The compounds of formula (Ia-2), which correspond to the compounds of formula (Ia) wherein at least one substituent selected from the group consisting of R11a and R15a, and R73 to R82 and R93 to R116 in R5a is a group represented by xe2x80x94OSi(R86)(R87)(R88)(R86, R87 and R88 have the same meanings as the above defined R20, R21, and R22, respectively);
the compounds of formula (Ia-3), which correspond to the compounds of formula (Ia) wherein at least one substituent selected from the group consisting of R11a and R15a, and R73 to R82 and R93 to R116 in R5a is an acyloxy group (the acyloxy group is a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aroyloxy group, or a substituted or unsubstituted lower alkenoyloxy group); and the compounds of formula (Ia-4), which correspond to the compounds of formula (Ia) wherein at least one substituent selected from the group consisting of R11a and R15a, and R73 to R82 and R93 to R116 in R5a is a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, or a substituted or unsubstituted aryloxy group, or R19a is a substituted or unsubstituted lower alkoxyl group can be synthesized from the compounds of formula (Ia-1) wherein at least one substituent selected from the group consisting of R11a, R15a, and R19a, and R73 to R82 and R93 to R116 in R5a is a hydroxyl group.
Further, compounds wherein R5a is a group represented by xe2x80x94OSi(R86)(R87)(R88) (R86, R87, and R88 have the same meanings as the above defined R20, R21 and R22, respectively), an acyloxy group (the acyloxy group is a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aroyloxy group, or a substituted or unsubstituted lower alkenoyloxy group), a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, or a substituted or unsubstituted aryloxy group can be synthesized from a corresponding compound wherein R5a is a hydroxyl group.
In the reaction formulas shown in the following steps 1 to 3, a series of compounds wherein R5a is the same as the group of (K) as defined above are shown as examples of the compounds of formulas (Ia-1), (Ia-2), (Ia-3), and (Ia-4) (R107, R111, R113, and R114 are methyl groups, R108, R109, R110, R112, R115, and R116 are hydrogen atoms, and ---- in formula (K) is a single bond). 
(In the formulas, at least one group selected from the group consisting of R1-11, R1-15, R1-19, R1-80, R1-81, and R1-82 represents a hydroxyl group, at least one group selected from the group consisting of R2-11, R2-15, R2-80, R2-81, and R2-82 represents a group represented by xe2x80x94OSi(R86)(R87)(R88) (R86, R87 and R88 have the same meanings as the above defined R20, R21 and R22, respectively), at least one group selected from the group consisting of R3-11, R3-15, R3-80, R3-81, and R3-82 represents an acyloxy group (the acyloxy group has the same meaning as that defined above), at least one group selected from the group consisting of R4-11, R4-15, R4-19, R4-80, R4-81, and R4-82 represents a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, or a substituted or unsubstituted aryloxy group, R1-11, R2-11, R3-11, and R4-11 among the remaining substituents have the same meaning as the aforementioned R11a, R1-15, R1-80, R1-81, R1-82, R2-15, R2-80, R2-81, R2-82, R3-15, R3-80, R3-81, R3-82, R4-15, R4-19, R4-80, R4-81 and R4-82 have the same meaning as the aforementioned R15a, and R1-19 and R4-19 have the same meaning as the aforementioned R19a.)
 less than Step 1 greater than 
A compound of formula (Ia-2) can be synthesized by silylating the hydroxyl group of a compound of formula (Ia-1) using a suitable silylation reagent. As the silylation reagent, any of silylation reagents usually used for silylation of a hydroxyl group may be used. For example, the compound can be synthesized by allowing a compound of formula (Ia-1) to react with 1 to 100 equivalents of a silylation agent such as that of formula (R86)(R87)(R88)SiHal, (R86)(R87)(R88)SiOSO2CF3 (in the formulas, Hal represents a halogen atom having the same meaning as that defined above, and R86, R87, and R88 have the same meanings as the above defined R20, R21 and R22, respectively) or the like in an inert solvent such as acetonitrile, tetrahydrofuran, ether, dioxane, dimethylformamide, dimethyl sulfoxide, chloroform, or dichloromethane in the presence of 1 to 100 equivalents of a base such as imidazole, pyridine, triethylamine, ethyldiisopropylamine, N,N-dimethylaniline, or 2,6-lutidine. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
 less than Step 2 greater than 
A compound of formula (Ia-3) can be synthesized by acylating the hydroxyl group of a compound of formula (Ia-1) using a suitable acylation agent. As the acylation agent to be used, any of acylation agents usually used for acylation of a hydroxyl group may be used. For example, the compound can be synthesized by allowing a compound of formula (Ia-1) to react with 1 to 100 equivalents of an acid anhydride or an acid halide without a solvent or in a solvent such as N,N-dimethylformamide, chloroform, or dichloromethane in the presence of 1 equivalent to a solvent amount of a base such as pyridine, triethylamine, N,N-dimethylaniline, ethyldiisopropylamine or 4-dimethylaminopyridine. The acyl groups in the aforementioned acylation agents have the same meaning as the acyl group of the aforementioned acyloxy group.
Further, a compound of formula (Ia-3) can also be synthesized by allowing a compound of formula (Ia-1) to react with 1 to 100 equivalents of a carboxylic acid in a solvent such as N,N-dimethylformamide, chloroform or dichloromethane in the presence of 1 to 100 equivalents of a base such as pyridine, triethylamine, N,N-dimethylaniline, ethyldiisopropylamine, or 4-dimethylaminopyridine and 1 to 100 equivalents of a condensing agent such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or carbonyldiimidazole. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
 less than Step 3 greater than 
A compound of formula (Ia-4) can be synthesized by alkylating the hydroxyl group of a compound of formula (Ia-1) using a suitable alkylation reagent. As the alkylation reagent, any of alkylation reagents usually used for alkylation of a hydroxyl group may be used. For example, the compound can be synthesized by allowing a compound of formula (Ia-1) to react with 1 to 50 equivalents of dimethyl sulfate, diazomethane, trimethylsilyldiazomethane, an alkyl halide, an alkoxyalkyl halide, a trialkoxytetrafluoroborate or the like in an inert solvent such as methanol, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, chloroform, or dichloromethane in the presence of, if necessary, 1 to 50 equivalents of a base such as sodium hydride, silver oxide, potassium carbonate, diisopropylethylamine, pyridine, triethylamine, N,N-dimethylaniline, or 1,8-bis(dimethylamino)naphthalene. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
The compound of formula (Ia-4) can also be synthesized by allowing a compound of formula (Ia-1) to react with 1 to 50 equivalents of a substituted or unsubstituted aralkyl trichloroimidate or the like in an inert solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, chloroform, toluene, or dichloromethane in the presence of 0.01 to 50 equivalents of an acid such as camphorsulfonic acid or trifluoromethanesulfonic acid. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
Furthermore, the compound of formula (Ia-4) can be synthesized by allowing a compound of formula (Ia-1) to react with 1 to 50 equivalents of a substituted or unsubstituted aryl alcohol or the like in an inert solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, chloroform, or dichloromethane in the presence of 1 to 50 equivalents of a phosphine such as (C6H5)3P or (C4H9)3P and 1 to 50 equivalents of a regent such as diethylazodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperazine. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 100xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
The compounds of formula (Ia-6) (in the formula, R5-11 and R5-15 have the same meanings as the above defined R11a and R15a, R5-5 has the same meaning as the above defined R5a, R5-19 has the same meaning as the above defined R19a, and R5-18a has the same meaning as the above defined R26) that correspond to the compounds of formula (Ia) wherein R18a is a group represented by xe2x80x94CHxe2x95x90CHR89 (R89 has the same meaning as the above defined R26, and the configuration of the double bond may be either in Z or E, or a mixture thereof);
the compounds of formula (Ia-7) (in the formula, R5-11 and R5-15 have the same meanings as the above defined R11a and R15a, R5-5 has the same meaning as the above defined R5a, R5-19 has the same meaning as the above defined R19a, and R5-18b has the same meaning as the above defined R27) that correspond to the compounds of formula (Ia) wherein R18a is a group represented by xe2x80x94CHxe2x95x90NOR90 (R90 has the same meaning as the above defined R27, and as for the syn/anti isomerism resulting from the carbon/nitrogen double bond, the compounds may be a syn-isomer or anti-isomer or a mixture thereof); and
the compounds of formula (Ia-8) (in the formula, R5-11 and R5-15 have the same meanings as the above defined R11a and R15a, R5-5 has the same meaning as the above defined R5a, R5-19 has the same meaning as the above defined R19a, R5-18c has the same meaning as the above defined R28, and X3 has the same meaning as the above defined X1) that correspond to the compounds of formula (Ia) wherein R18a is a group represented by xe2x80x94CH(X3R5-18c)2 (in the formula, X3 has the same meaning as the above defined X1, and R5-18c has the same meaning as the above defined R28) can be prepared from the compounds of formula (Ia-5) (in the formula, R5-11 and R5-15 have the same meanings as the above defined R11a and R15a, R5-5 has the same meaning as the above defined R5a, and R5-19 has the same meaning as the above defined R19a) that correspond to the compounds of formula(Ia) wherein R18a is a formyl group according to the following method. 
(In the formulas, R5-11 and R5-15 have the same meanings as the above defined R11a and R15a, respectively, R5-5 has the same meaning as the above defined R5a, R5-19 has the same meaning as the above defined R19a, R5-18a has the same meaning as the above defined R26, R5-18b has the same meaning as the above defined R27, R5-18c has the same meaning as the above defined R28, and X3 has the same meaning as the above defined X1.)
 less than Step 4 greater than 
A compound of formula (Ia-6) can be prepared by dissolving a compound of formula (Ia-5) in an inert solvent such as toluene, methanol, acetonitrile, tetrahydrofuran, ether, dioxane, dimethylformamide, dimethyl sulfoxide, chloroform or dichloromethane, and allowing the compound to react with 1 to 100 equivalents of a compound represented by the general formula (C6H5)3Pxe2x95x90CHR89 (R89 has the same meaning as the above defined R26) or allowing the compound to be treated with 1 to 100 equivalents of a reagent represented by the formula (R91O)2P(O)CH2R89 (R89 has the same meaning as the above defined R26, and R91 represents a lower alkyl group having the same meaning as that defined above) or the like in the presence of 1 to 100 equivalents of a base such as sodium hydride, sodium amide, or sodium alkoxide. The reaction temperature is preferably xe2x88x9278xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 100 hours.
 less than Step 5 greater than 
A compound of formula (Ia-7) can be synthesized by adding 1 to 100 equivalents of a compound represented by the formula H2NOR90 (R90 has the same meaning as the above defined R27) to a compound of formula (Ia-5) in an inert solvent such as methanol, ethanol, acetonitrile, tetrahydrofuran, ether, dioxane, dimethylformamide, dimethyl sulfoxide, chloroform, or dichloromethane in the presence of 1 to 100 equivalents of a base such as pyridine, triethylamine, ethyldiisopropylamine, or 4-dimethylaminopyridine. The reaction temperature is preferably xe2x88x9250xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 100 hours.
 less than Step 6 greater than 
A compound of formula (Ia-8) can be prepared by allowing a compound of formula (Ia-5) to react with 1 equivalent to a solvent amount of a lower alcohol compound or a lower thiol compound represented by the formula R92X4H or HX4(CH2)tX4H (R92 represents a lower alkyl group having the same meaning as that defined above, X4 has the same meaning as the above defined X1, and t is 2 or 3) without a solvent or in an inert solvent such as acetonitrile, tetrahydrofuran, ether, dioxane, dimethylformamide, dimethyl sulfoxide, chloroform or dichloromethane. In the reaction, a catalytic amount to 100 equivalents of an acid such as hydrochloric acid, p-toluenesulfonic acid, or trifluoroborane ether complex can be added as required. The reaction temperature is preferably xe2x88x9260xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 100 hours.
The compounds of formula (Ia-10) (in the formula, R9-11 and R9-15 have the same meanings as the above defined R11a and R15a, R9-18 has the same meaning as the above defined R18a, and R9-19 has the same meaning as the above defined R19a) that correspond to the compounds of formula (Ia) wherein R5a is, for example, a group represented by the following formula: 
(in the formula, ---- has the same meaning as that defined above, R9-93 has the same meaning as the above defined R93, and R9-73, R9-74, and R9-94 have the same meanings as the above defined R73, R74, and R94, respectively) can be prepared from the compounds of formula (Ia-9) (in the formula, R9-11 and R9-15 have the same meanings as the above defined R11a and R15a, R9-18 has the same meaning as the above defined R18a, and R9-19 has the same meaning as the above defined R19a) that correspond to the compounds of formula(Ia) wherein R5a is a hydroxyl group according to the following method. 
(In the formula, ---- represents a single bond or a double bond, R9-11 and R9-15 have the same meanings as the above defined R11a and R15a, R9-18 has the same meaning as the above defined R18a, R9-19 has the same meaning as the above defined R19a, R9-94 has the same meaning as the above defined R94, R9-74 has the same meaning as the above defined R74, R9-75 has the same meaning as the above defined R75, and R9-93 has the same meaning as the above defined R93.)
 less than Step 7 greater than 
A compound of formula (Ia-10) can be synthesized by dissolving a compound of formula (Ia-9) in an inert solvent such as toluene, acetonitrile, tetrahydrofuran, ether, dichloromethane, or 1,2-dichloroethane and allowing the compound to react with 1 to 100 equivalents of a compound represented by the following formula: 
(in the formula, R9-93 has the same meaning as the above defined R93, R9-73 and R9-74 have the same meanings as the above defined R73 and R74, and R9-94 has the same meaning as the above defined R94) in the presence of 0.01 to 100 equivalents of an acid such as camphorsulfonic acid, p-toluenesulfonic acid and triphenylphosphine hydrobromide. The reaction temperature is preferably xe2x88x9230xc2x0 C. to 150xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
Further, the compound can also be synthesized by allowing the starting material to react with 1 to 100 equivalents of an ordinary saccharide donor represented by the following formula: 
(in the formula, R95b represents halogen, a phenylthio group, an alkylthio group, a group represented by CCl3C(xe2x95x90NH)xe2x80x94Oxe2x80x94 or the like, R9-93 has the same meaning as the above defined R93, and R9-73, R9-74, and R9-94 have the same meanings as the above defined R73, R74 and R94, respectively) or the like in an inert solvent such as toluene, acetonitrile, tetrahydrofuran, ether, dichloromethane or 1,2-dichloroethane in the presence of 0.01 to 10 equivalents of an activating agent such as trimethylsilyl triflate, a trifluoroborane ether complex, silver perchlorate/tin chloride, silver carbonate, or methyl triflate. A drying agent such as molecular sieves may be used, if necessary. The reaction temperature is preferably xe2x88x9278xc2x0 C. to 100xc2x0 C., and the reaction time is usually 5 minutes to 150 hours.
Compounds having a substituent of formula (H), (J), or (K) can also be synthesized by repeating the above step 7. It is also possible to obtain a compound having a substituent of formula (G-2) by performing the process shown in the above step 7 using an ordinary saccharide donor represented by formula (L) wherein R95b has the same meaning as that defined above and R9-94 is a substituted or unsubstituted lower alkanoyloxy group.
Isolation and purification of products obtained in the aforementioned preparation methods can be performed by a suitable combination of techniques used for ordinary organic synthesis such as filtration, extraction, washing, drying, concentration, and crystallization, as well as various kinds of chromatography techniques. Further, intermediate products can also be used in a subsequent reaction without particular purification. The compounds of the present invention represented by formula (Ia) may exist in the forms of salts, and examples thereof include those exemplified for the compounds represented by formula (I). For preparation of the salts of the compounds of formula (Ia), a compound of formula (Ia) in a free form is dissolved or suspended in a suitable solvent, a suitable acid or base is added thereto, and the produced salt can be isolated or purified, as required. If a desired salt is produced as a target product in a final step, it is also possible to isolate or purify the salt, per se. An appropriate salt can be converted into a compound in the free form, and then a suitable acid or base can be added to the free compound for conversion into a desired salt.
The compounds represented by formula (Ia) and salts thereof according to the present invention are useful as an active ingredient of medicaments such as agents for inducing apoptosis, antibacterial agents, anticancer agents, anti-Piroplasma agents, anti-parasitic agents, anti-inflammatory agents, hypolipidemic agents or the like. However, use of the compounds of the present invention is not limited to the aforementioned medicaments.